T3D-959 is an orally delivered, small molecule, dual nuclear receptor agonist aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer?s disease (AD). Exploratory human clinical test results (Phase 2a study) of T3D-959 in mild to moderate severity AD patients have shown multiple efficacy signals indicating a potential to slow, stop or reverse the course of disease. The next stage in the development of this drug to eventual market is to validate these observed efficacy signals in a larger and longer Phase 2 clinical trial that is statistically powered to see significant differences versus placebo in outcome measures of cognitive and functional improvement. The objective of the proposed project is to execute and complete this study of T3D-959 in AD patients. The funded parent award project had a design that was limited to the assessment of a single dose strength. The new proposed project, the PIONEER Study (Prospective therapy to Inhibit and Overcome Alzheimer?s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration) will assess multiple dose strengths with greater statistical powering to identify the most safe and effective dose or doses to use in subsequent Phase 3 testing. The clinical trial will be a randomized, double-blind, placebo- controlled, multi-center Phase 2 trial involving 256 mild to moderate AD patients (MMSE=16-26) dosed orally once-a-day for 24-weeks in 4 parallel arms (T3D-959 active arms of 15mg, 30mg and 45mg QD and a placebo arm in a 1:1:1:1 ratio). Co-primary outcome measures will include the ADAS-cog11 cognition and global function CGIC measures. Secondary outcome measures will include executive function as measured by DSST and change from baseline in plasma A? 42/40 ratio. Exploratory outcome measures will include change from baseline in plasma NfL and Tau between subjects treated with T3D-959 compared to placebo, evaluation of the effect of T3D-959 compared with placebo on apathy as measured by the Neuropsychiatric Inventory (NPI), on functional decline as measured with the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL), on executive function changes on verbal fluency, on plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl). The study is powered for the primary analysis on ADAS-cog11 to have approximately 90% power for each of the comparisons with placebo (and similarly for the co-primary endpoint, CGIC), at 1-sided alpha = 0.0167 (= 0.05/3) accounting for a Bonferroni adjustment for 3 comparisons and overall alpha 1-sided 0.05. With a 2.5- unit treatment difference (in change from baseline) between each dose group and placebo and standard deviation (of changes from baseline) of 4 (as observed in the exploratory Phase 2a trial of T3D-959), 90% power will be provided by approximately 64 evaluable subjects per arm (PASS V14.0.5). Statistically significant improvement in the co-primary outcome measures will increase the likelihood that PIONEER is deemed as Phase 3-enabling and increase the likelihood of being given Breakthrough Therapy Designation by the FDA.